Study Assesses Predictive Markers of Resmetirom Histological Response in MAESTRO-NASH

Rohit Loomba, MD

Credit: ACG

Findings from a recent study are providing clinicians with an overview of the association between changes in alanine aminotransferase (ALT), Fibroscan controlled attenuation parameter (CAP), and Fibroscan vibration-controlled transient elastography (VCTE) with histological response to resmetirom (Rezdiffra) in the phase 3 MAESTRO-NASH trial.

The research was presented at Digestive Disease Week (DDW) 2024 in Washington, DC, this weekend by Rohit Loomba, chief of the division of gastroenterology and hepatology and professor of medicine at the University of California at San Diego.

An ongoing 54-month, randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and fibrosis, MAESTRO-NASH enrolled 966 patients and randomized them in a 1:1:1 ratio to treatment with resmetirom 80 mg, resmetirom 100 mg, or placebo administered once daily. It is one of 18 clinical studies in the oral, thyroid hormone receptor (THR)-β selective agonist’s clinical development program and was used to support resmetirom’s historic FDA approval in March.

Of note, the decision was an accelerated approval and is contingent upon verification and description of resmetirom’s clinical benefit in ongoing confirmatory trials, including MAESTRO-NASH, one of 4 phase 3 studies supporting the approval for in adult patients with NASH and fibrosis.

Histologic endpoints were assessed after 52 weeks, with dual primary endpoints for NASH resolution with no worsening of fibrosis or ≥1-stage reduction in fibrosis with no worsening of NASH at week 52 achieved with both resmetirom 80mg and 100mg.

Patients with biopsy-confirmed NASH with fibrosis had high metabolic risk including obesity (mean BMI, 36), type 2 diabetes (70%), hypertension (78%), and 10-year ASCVD risk score >14. Baseline mean FibroScan VCTE was 13.3 (Standard deviation [SD], 6.8), 13.6 (SD, 7.1), and 12.9 (SD, 5.6) kPa for the resmetirom 80mg, resmetirom 100mg, and placebo groups. Baseline ELF across all fibrosis groups was 9.8 (SD, 0.87) and FIB-4 across all dose groups was 1.3.

Results presented at DDW showed both doses of resmetirom significantly reduced ALT by approximately 30% relative to placebo. In resmetirom-treated patients, greater reductions in ALT were associated with increased NASH resolution and fibrosis improvement on biopsy.

For resmetirom-treated patients without a reduction in ALT, the NASH resolution and fibrosis improvement responses were predicted to be greater than the mean placebo biopsy responses. CAP improved with resmetirom treatment and predicted both NASH resolution and fibrosis improvement responses. However, investigators pointed out even no change in CAP predicted biopsy responses greater than the mean for placebo, and a CAP improvement in placebo patients did not predict fibrosis improvement on biopsy.

Additionally, VCTE improved over time relative to placebo in patients treated with resmetirom. Of note, even those with no VCTE improvement had greater NASH resolution and fibrosis improvement responses than the mean placebo response rates. However, investigators pointed out VCTE improvement was poorly predictive of a placebo fibrosis improvement or NASH resolution response, and worsening of VCTE in placebo patients predicted a lower-than-average NASH resolution and fibrosis improvement.

References:

1. ^{Loomba R, Schattenberg J, Taub R, et al. ALT, FIBROSCAN VCTE, AND FIBROSCAN CAP AS PREDICTIVE MARKERS OF RESMETIROM BIOPSY RESPONSE. Abstract presented at Digestive Disease Week (DDW) 2024 Annual Meeting. Washington, DC. May 17-21, 2024.}
2. ^{Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed May 19, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}